Suppression of gastric acid which attacks the gastric mucosa is effective in the treatment of digestive disorders, such as gastritis, dyspepsia, gastric hyperacidity, heartburn, gastric oppression, and peptic ulcer. Antacids, histamine H.sub.2 -receptor antagonists, anticholinergics, antigastrins, muscarine receptor antagonists, proton pump inhibitors, etc. have been used for this purpose.
The histamine H.sub.2 -receptor antagonists, for example, cimetidine, ranitidine, nizatidine and famotidine, antagonize histamine at the H.sub.2 -receptors of stomach cells to inhibit gastric acid secretion. The antacids directly neutralize the gastric acid that has been secreted or is being secreted.
Hence, simultaneous administration of a histamine H.sub.2 -receptor antagonist and an antacid is expected to produce high therapeutic effects, immediately neutralizing the secreted gastric acid while inhibiting gastric acid secretion, thereby complementarily eliminating gastric acid, which is a large cause of stimulation on the gastric mucosa.
Combinations of histamine H.sub.2 -receptor antagonists and antacids are taught in the following literature.
German Patent 3710462 teaches a pharmaceutical composition containing a histamine H.sub.2 -receptor antagonist and an antacid and having a cell protecting activity, showing a suspension containing 0.4 g of cimetidine, 6.3 g of aluminum hydroxide gel, and 1.5 g of magnesium hydroxide per 10 ml.
PCT International Publication Pamphlet 92/00102 and 93/12779 disclose tablet, etc. containing 2 mg of famotidine, 750 mg of aluminum hydroxide, and 750 mg of magnesium hydroxide as a pharmaceutical composition comprising a histamine H.sub.2 -receptor antagonist and an antacid, which has its equilibrium pH, acid neutralizing capacity and gastric duration optimally adjusted so as to have a pH level substantially equal to the pH level based on the pKa value of the histamine H.sub.2 -receptor antagonist.
PCT International Publication Pamphlet 93/21932 teaches the effect of a combined use of 400 mg of cimetidine and 30 ml of Maalox Plus oral liquid (magnesium hydroxide and aluminum hydroxide) on a patient suffering from heartburn.
An unexamined published Japanese patent application No. 7-165596 discloses tablets each containing 31.5 mg of ranitidine hydrochloride, 125 mg of magnesium aluminium silicate, 100 mg of magnesium aluminate, and 50 mg of magnesium oxide as a pharmaceutical composition for oral administration containing ranitidine or a pharmaceutically acceptable salt thereof, magnesium aluminium silicate, magnesium aluminate, and magnesium oxide.
Histamine H.sub.2 -receptor antagonists gradually increase the gastric pH when orally administered. Taking famotidine for an instance, after 20 mg is orally given, the pH gradually rises, reaches a plateau at pH 6 after about 3 hours, and is maintained in the range of from 5 to 6 over about 9 hours (Ikezoe, et al., Dai 12-kai kokusai syokakibyo gakkai). Antacids, which are a kind of alkali, neutralize gastric acid through acid-alkali reaction immediately after administration.
Therefore, it is desirable for the antacid to be combined with a histamine H.sub.2 -receptor antagonist to be capable of neutralizing gastric acid immediately after administration and retaining the gastric pH within an optimum range of from 3 to 5 for at least about 3 hours' duration, by the end of which the histamine H.sub.2 -receptor will have come to manifest its full effects. However, an excessive pH rise, especially in the initial pH immediately after administration is unfavorable because of the possibility of inducing gastric acid secretion as a rebound phenomenon (refer to Goodman and Gilman (ed.), The pharmacological Basis of Therapeutics of 7th Ed., pp 1209-1219, Hirokawa Shoten (May 25, 1988)).
That is, it has been demanded to develop a pharmaceutical composition in which an H.sub.2 -receptor antagonist is combined with such an antacid as (1) exerts a prompt neutralizing action without increasing the initial pH immediately after administration more than necessary and (2) sustains the optimum pH of 3 to 5 for about 3 hours, duration from administration, whereby the conditions of a patient will be improved promptly, and the effects will last for more than half a day.
However, none of the solid preparations comprising a histamine H.sub.2 -receptor antagonist and an antacid that have been reported to date satisfies: the above requirements.